This is a revised application for continued support of a Program Project Grant in an NICHD-funded Mental Retardation Research Centers. The program, whose goal is to better understand the biochemical defects and pathogenesis of several inborn errors that can cause mental retardation, developmental disability and/or early death, comprises five projects. Disorders to be studied are glutaric acidemia types I and II, homocystinuria due to cystathionine beta-synthase deficiency,a nd propionic acidemia. The investigators, Drs Goodman, Frerman, Kraus and Koeller, have contiguous laboratories in the MRRC; share interests, methods and equipment; and interact closely on a daily basis. The project by Goodman is on glutaric acidemia type I (GAI), a disorder which causes mental retardation and striatal degeneration, and examines the mutations that cause GAI, the relationship between specific mutations and the biochemical and clinical phenotype, and structure-function aspects of glutaryl-coenzyme A dehydrogenase (GCDH), the enzyme whose deficiency causes the disease. Projects by Frerman and Goodman, focus on the biochemistry, molecular biology, and mutations of electron transfer flavoprotein (ETF) and ETF:ubiquinone oxidoreductase (ETF:QO), seeking to determine why mutations cause enzyme deficiency, and why enzyme deficiency causes clinical manifestations of glutaric acidemia type II (GA2). In this vein, the project by Goodman,also seeks to create a murine model of ETF:QO deficiency. The project by Kraus examines the biochemistry an molecular biology of cystathionine beta-synthase (CBS) and genotype-phenotype aspects of human CBS deficiency; and the project by Kraus examines propionyl-CoA carboxylase (PCC) and human PCC deficiency. The thread that unites these projects is the attempt to delineate why impaired enzyme function causes disease, information that is essential to formulate rational approaches to therapy.